Penicillin
Sir Alexander Fleming (6 August 1881 – 11 March 1955)
The discovery of penicillin is attributed to Scottish scientist and nobel laureate Alexander Fleming in 1928. The development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey.
However, several others reported the bacteriostatic effects of Penicillium earlier than Fleming. The first published reference appears to have been in 1875, in the Royal Society in London by John Tyndall. Ernest Duchesne documented it in his 1897 paper which was not accepted by the Institut Pasteur because of his young age. In March 2000, doctors at the San Juan de Dios Hospital in San José, Costa Rica published the manuscripts of the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (1887–1944). They reported Picado's observations on the inhibitory actions of fungi of the genus Penic between 1915 and 1927. Picado reported his discovery to the Paris Academy of Sciences, yet did not patent it, even though his investigations started years before Fleming's.
Fleming recounted that the date of his breakthrough was on the morning of Friday, September 28, 1928. At his laboratory in the basement of St. Mary's Hospital in London (now part of Imperial College), Fleming noticed a halo of inhibition of bacterial growth around a contaminant blue-green mold in a Staphylococcus plate culture. Fleming concluded that the mold was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture and discovered that it was a Penicillium mold, now known to be Penicillium notatum. Charles Thom, an American specialist working at the U.S. Department of Agriculture was the acknowledged expert, and Fleming referred the matter to him. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the Penicillium mold. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, and noted its laboratory value in the isolation of "Bacillus influenzae" (now Haemophilus influenzae). After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria, and stopped studying it after 1931. He restarted clinical trials in 1934, and continued to try to get someone to purify it until 1940.
In 1930 Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to treat sycosis barbae – eruptions in beard follicles – but was unsuccessful, probably because the drug did not get deep enough. Moving on to ophthalmia neonatorum – a gonococcal infection in babies – he achieved the first cure on 25 November 1930. He cured four patients (one adult, three babies) of eye infections, although a fifth patient was not so lucky.
In 1939, Australian scientist Howard Florey (later Baron Florey) and a team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the in vivo bactericidal action of penicillin. Their attempts to treat humans failed due to insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved it harmless and effective on mice.
Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford, England. On March 14, 1942, John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.
The challenge of mass-producing the drug was daunting. On March 14, 1942 the first patient was treated for streptococcal septicemia with U.S.-made penicillin produced by Merck < Co. Half of the total supply produced at the time was used on that one patient. By June 1942 there was just enough U.S. penicillin available to treat ten patients. A moldy cantaloupe in a Peoria, Illinois market in 1943 was found to contain the best and highest-quality penicillin after a world-wide search. The discovery of the cantaloupe, and the results of fermentation research on corn-steep liquid at the Northern Regional Research Laboratory at Peoria, Illinois, allowed the USA to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944. Penicillin was being mass-produced in 1944
During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds among Allied forces, saving an estimated 12%–15% of lives.[citation needed] Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug, necessitating frequent dosing. Penicillin are actively secreted, and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times, it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused.
This was not a satisfactory solution, so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing penicillin's concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined. Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.
The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in the early 1940s. A team of Oxford research scientists led by Australian Howard Florey, Baron Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass-producing the drug. Chemist Robert Burns Woodward at Harvard University completed the first total synthesis of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work, and, after WWII, Australia was the first country to make the drug available for civilian use. Penicillin has since become the most widely used antibiotic to date, and is still used for many Gram-positive bacterial infections.